Studying the thermodynamics of protein-DNA association, we have reported the effects of a base-pair substitution and mutation of an amino acid (Glu27 yields Val27) at a single site in the Cro-DNA complex (Proc. Natl. Acad. Sci USA, 8180, 1992). This work raised the question of whether these perturbation arose from interactions of the reactants with the solvent or from interactions within the protein-DNA complex or some combination thereof. In order to address these questions we have carried out model system studies of small molecular binding to alpha- and beta- cyclodextrins which are hollow truncated conical substrates with a moderately hydrophobic core. This receptor exerts stringent size requirements upon the bound molecule, at the level of a the radius of a single atom. The most important result of these studies is that the changes in the thermodynamic parameters are associated with the portions of the ligand molecule that undergo an alteration in its environment, thus the observed perturbations are at a sub-molecular level. We have obtained complete thermodynamic profiles for several examples of a single hydrogen-bond and a single hydrophobic interaction. For a closely related series of compounds, differences in interactions with the solvent are minimal, therefore indicating that the thermodynamic effects we have observed in our protein-DNA studies reflect differing interactions within the protein-DNA complex. Having gained this quantitative prerequisite knowledge from these model system studies, we are now in a position to carry out interpretable further studies altering the remaining base-pairs of the operator DNA.